Genetic Variant TBP:c.-327T>C (chr6-170554285-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_003194.5(TBP):c.-327T>C variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.26 in 152,254 control chromosomes in the GnomAD database, including 6,254 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.26 ( 6250 hom., cov: 33)

Exomes 𝑓: 0.32 ( 4 hom. )

Consequence

TBP
NM_003194.5 upstream_gene

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.0280

Publications

12 publications found

Variant links:

Genes affected

TBP (HGNC:11588): (TATA-box binding protein) Initiation of transcription by RNA polymerase II requires the activities of more than 70 polypeptides. The protein that coordinates these activities is transcription factor IID (TFIID), which binds to the core promoter to position the polymerase properly, serves as the scaffold for assembly of the remainder of the transcription complex, and acts as a channel for regulatory signals. TFIID is composed of the TATA-binding protein (TBP) and a group of evolutionarily conserved proteins known as TBP-associated factors or TAFs. TAFs may participate in basal transcription, serve as coactivators, function in promoter recognition or modify general transcription factors (GTFs) to facilitate complex assembly and transcription initiation. This gene encodes TBP, the TATA-binding protein. A distinctive feature of TBP is a long string of glutamines in the N-terminus. This region of the protein modulates the DNA binding activity of the C terminus, and modulation of DNA binding affects the rate of transcription complex formation and initiation of transcription. The number of CAG repeats encoding the polyglutamine tract is usually 25-42, and expansion of the number of repeats to 45-66 increases the length of the polyglutamine string and is associated with spinocerebellar ataxia 17, a neurodegenerative disorder classified as a polyglutamine disease. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2016]

TBP Gene-Disease associations (from GenCC):

spinocerebellar ataxia type 17
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Laboratory for Molecular Medicine, Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)

TBP links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.9).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.71 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBP	NM_003194.5 link	c.-327T>C		upstream_gene_variant		ENST00000392092.7	NP_003185.1
TBP	NM_001172085.2 link	c.-185T>C		upstream_gene_variant			NP_001165556.1

Ensembl

Gene	Transcript	HGVSc	Effect	TSL	MANE	Protein
TBP	ENST00000392092.7 link	c.-327T>C	upstream_gene_variant	1	NM_003194.5	ENSP00000375942.2
TBP	ENST00000230354.10 link	c.-330T>C	upstream_gene_variant	1		ENSP00000230354.5
TBP	ENST00000421512.5 link	c.-327T>C	upstream_gene_variant	1		ENSP00000400008.1
TBP	ENST00000540980.5 link	c.-185T>C	upstream_gene_variant	2		ENSP00000442132.1

Frequencies

GnomAD3 genomes

AF:

0.260

AC:

39511

AN:

152062

Hom.:

6251

Cov.:

show subpopulations

Gnomad AFR

AF:

0.122

Gnomad AMI

AF:

0.355

Gnomad AMR

AF:

0.273

Gnomad ASJ

AF:

0.229

Gnomad EAS

AF:

0.729

Gnomad SAS

AF:

0.346

Gnomad FIN

AF:

0.268

Gnomad MID

AF:

0.203

Gnomad NFE

AF:

0.298

Gnomad OTH

AF:

0.272

GnomAD4 exome

AF:

0.324

AC:

AN:

Hom.:

Cov.:

AF XY:

0.280

AC XY:

AN XY:

show subpopulations

African (AFR)

AF:

0.500

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AF:

1.00

AC:

AN:

South Asian (SAS)

AF:

0.00

AC:

AN:

European-Finnish (FIN)

AF:

0.0833

AC:

AN:

Middle Eastern (MID)

AF:

0.500

AC:

AN:

European-Non Finnish (NFE)

AF:

0.375

AC:

AN:

Other (OTH)

AF:

0.500

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.260

AC:

39510

AN:

152180

Hom.:

6250

Cov.:

AF XY:

0.261

AC XY:

19444

AN XY:

74400

show subpopulations

African (AFR)

AF:

0.122

AC:

5063

AN:

41538

American (AMR)

AF:

0.273

AC:

4182

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.229

AC:

794

AN:

3470

East Asian (EAS)

AF:

0.729

AC:

3757

AN:

5152

South Asian (SAS)

AF:

0.345

AC:

1662

AN:

4824

European-Finnish (FIN)

AF:

0.268

AC:

2840

AN:

10598

Middle Eastern (MID)

AF:

0.201

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.298

AC:

20249

AN:

67982

Other (OTH)

AF:

0.275

AC:

581

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1454

2907

4361

5814

7268

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

418

836

1254

1672

2090

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.268

Hom.:

3084

Bravo

AF:

0.261

Asia WGS

AF:

0.487

AC:

1691

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

0.48

(source)

DANN

Benign

0.30

PhyloP100

-0.028

PromoterAI

0.014

Neutral

(source)

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over